Warm-blooded animals are subject to attack by parasites, and man has long sought to combat such parasites afflicting domestic companion animals, farmed livestock and exotic animals, to alleviate suffering and for commercial gain. The manner of attack by the parasites, and the identification of a sensitive stage in the life cycle of the parasite, may influence greatly the choice of combating agent. Thus percutaneous treatments using topically applied preparations such as lotions, paints, creams, gels, dusting powders, “pour-ons” and dips are commonly suitable for ectoparasites, but combating endoparasites requires careful selection of the method of administration and the delivery system. Oral drenches, pastes, boluses, tablets, and granules for incorporating into feed mixes are known methods capable of being used by the animal husbandrymen, but other methods which are intended to avoid use of the gastrointestinal route are typically administered by qualified practitioners. Such other methods include use of aerosols, and parenteral drug compositions which are selectively prepared as solution or suspension or micronised powder formulations intended for subcutaneous, intracutaneous, and intramuscular injection according to the intended delivery regime. These last methods require special care in formulation to avoid irritation at the site of injection or possible adverse allergic or pyrogenic reactions.
Formulations are typically prepared using aqueous or non-aqueous (“solvent”) vehicles. The latter class may comprise physiologically tolerable alcohols, glycols, esters, a limited range of organic aromatic solvents, and vegetable oils and extracts or modified forms thereof. In selecting vehicles, the skilled worker has to consider a number of issues including, solubility of the intended active ingredient(s), the affinity of the drug to certain vehicles, whether it will affect any essential auxiliaries, pH, stability over time, viscosity, and naturally the risk of any toxic effect upon the animal to be treated. In the case of a “pour-on” formulation, the ability to facilitate the transfer of the active ingredient or ingredients through the skin and into the bloodstream to provide an efficacious dose is an essential feature of the composition. Therefore, formulation of a parasiticide is a complex task.
Traditional parasiticides include chemical agents such as the benzimidazoles, and carbamates, and plant extracts such as the pyrethroids, which tend to be used to combat ectoparasites such as ticks and mites.
The salicylanilides, tend to be effective against fungal attack, but the chemically modified derivative closantel is an effective worming agent. Closantel is described in U.S. Pat. No. 4,005,218 and in the literature, e.g. J. Guerrero et al, J. Parasitol. 68,616, (1983); H. Van den Bossche et al, Arch. Int. Physiol. Biochim, 87, 851(1979); H. J. Kane et al, Mol. Biochem. Parasitol. 1, 347(1980).
Closantel is typically administered by the oral route e.g. as a bolus, or oral drench, or parenterally as an injection solution. WO 95/05812 suggests that an injectable anthelmintic composition containing abamectin and closantel can be produced with glycerol formal optionally using a glycol-based solvent such as polyethylene glycol 400, or propylene glycol. However, because the topical route of administration is generally slower than any other routes (injection or oral route), absorption of closantel through the skin would be expected to be very slow, therefore closantel plasma levels would be expected to be lower than that obtained by delivery by any other route.
Closantel is also very hydrophobic and is very quickly and substantially bound to plasma proteins, this again would suggest to those skilled in the art that administration by topical means would reduce the achievable plasma concentration.
Therefore, currently there is no known commercial formulation adapted for administration of closantel as a pour-on.
The avermectins are very potent antiparasitic agents which are useful against a broad spectrum of endoparasites and ectoparasites in mammals as well as having agricultural uses against various parasites found in and on crops and soil. The basic avermectin compounds are isolated from the fermentation broth of the soil micro-organism Streptomyces avermitilis and these compounds are described in U.S. Pat. No. 4,310,519. Furthermore, derivatives of these basic avermectin compounds have been prepared by a variety of chemical means.
Some of the avermectin group of compounds contain a 22,23-double bond and others contain a disaccharide at the 13-position which consists of α-L-oleandrosyl-α-L-oleandrosyl group. One or both saccharide units can be removed forming a monosaccharide or an aglycone (where both saccharides are removed) as described in U.S. Pat. No. 4,206,205. The aglycone derivatives possess a hydroxy group at the 13 position which may be removed to form the 13-deoxy compound as described in the U.S. Pat. No. 4,171,314 and U.S. Pat. No. 4,173,571. Acylaton of hydroxy groups on the avermectin compounds and derivatives can be carried out as described in U.S. Pat. No. 4,201,861.
The milbemycin series of compounds, disclosed in U.S. Pat. No. 3,950,360, are structurally similar to the avermectin family in that they contain the sixteen membered macrocyclic ring. However, they do not contain the disaccharide sub-unit and there are differences in the substituent groups.
Ivermectin, disclosed in U.S. Pat. No. 4,199,569, is prepared by the selective reduction of the 22, 23 double bond of the avermectin compounds. Ivermectin is a mixture of 22,23-dihydro Avermectin B1a and B1b in a ratio of at least 80:20.
Ivermectin is an especially preferred active component in pesticidal compositions, and there is extensive literature on its activity, demonstrating its efficacy against internal and external parasites, and its ability to interfere in the life cycle of certain parasites. The Merck Index (1996) cites several references including J. C. Chabala et al, J. Med. Chem. 23, 1134 (1980); J. R. Egerton et al, Brit. Vet. J. 136, 88 (1980); W. C. Campbell et al, Science 221, 823-828 (1983) to mention but a few.
Formulation of ivermectin for the purposes of delivery in a variety of presentations, e.g. as an oral drench, pour-on, parenteral formulations, granules for adding to feed, and syringeable pastes has proved highly challenging and numerous patents have been published on its use. Ivermectin exhibits a lipophilic character but it can be solvated in aqueous systems, and various patents describe special solvent systems for use in its formulation. Thus reference may be made at least to EP 0 045 655, and EP 0 146 414 for example.
Although ivermectin is surprisingly effective, and has enjoyed a long period of commercial success, there remains a keen interest in exploiting ivermectin against a wider range of parasites and in overcoming tolerance by some parasites which demands higher amounts of ivermectin to be delivered. Taking into account the fact that a significant volume of use of ivermectin is in protecting and treating animals intended for slaughter for human consumption, there are constraints on the residual amount of active components such as ivermectin in the carcass of such an animal. Therefore, high loadings of ivermectin, even if technically feasible, in a delivery system are not necessarily the optimum solution.
Combination formulations are also desirable taking account of acquired tolerance or resistance in pests to prolonged usage of other more traditional parasiticidal agents. This phenomenon is well documented, e.g. in relation to worming compositions. Synergistic effects or complementary effects of combined parasiticidal agents have been observed as a route to combating the aforesaid tolerance problem. Synergistic anthelmintic compositions are discussed in WO 94/28887, which focuses on substituted mono- and bisphenols, salicylanilides, benzene sulphonamides, halogenated be benzimidazoles, benzimidazoles, and benzimidazole carbamates.
The opportunity to combine the use of avermectins with other parasiticidal agents has been explored already. Thus one finds that skin-absorbable pour-on formulations containing triclabendazole, optionally containing an avermectin, tetramisole or levamisole have been proposed in WO 0061068. An injectable formulation containing closantel together with an avermectin or milbemycin has been proposed in WO 95/05812. Formulations of the pour-on and injectable type are suggested in WO 01/60380, which comprise use of a pyrrolidone solvent and a bridging solvent such as a xylene, optionally including a further solubility agent such as propylene glycol caprylic acids and esters or peanut oil. This special solvent system is needed to address the difficulties of formulating differing parasiticidal agents such as closantel and ivermectin together. No disclosure of the efficacy of these formulations is made.
Other non-aqueous pour-on formulations are disclosed in WO97/13508, using a range of solvents, particularly polyalcohols, their ethers and mixtures thereof, optionally in combination with various co-solvents. Whilst that reference does present results of trials of formulations disclosed therein they show limited success in achieving transfer of the active components into the bloodstream of the treated animal as discussed hereafter in the comparative Example.
Salicylanilide derivatives such as closantel provide useful control over a range of parasites and are especially useful against liver fluke. The avermectin group of anti-parasitic compounds of which ivermectin is the best known example, provide complementary protection against many other parasites such as roundworms. Therefore, there are advantages to be gained if a combination of these drugs could be provided in a form that can be conveniently administered to livestock and which will provide effective control of parasitic infection.
In particular the provision of an effective pour-on formulation containing closantel and ivermectin is therefore a highly desirable goal. The provision of a satisfactory formulation is problematical because the solubility regime for each drug is different. An alkaline system provides the optimum pH for closantel, whereas ivermectin requires an acidic medium for satisfactory dissolution.